This invention relates to a novel process for the preparation of pyrazoles. In particular the present invention relates to a novel process for the preparation of pyrazole intermediates useful in the synthesis of 4-alkylpiperazinylsulfonylphenyl- and 4-alkylpiperazinylsulfonyl pyridinyl-dihydropyrazolo[4,3-d]pyrimidin-7-one derivatives which are potent and selective cGMP PDE5 inhibitors.
A general synthetic route for the preparation of 4-alkylpiperazinylsulfonylphenyl-dihydropyrazolo[4,3-d]pyrimidin-7-one derivatives is described in EP 812 845, EP 994 115 and W098/49166, and for analogues thereof is described in WO 99/54333. The synthesis involves a coupling reaction between an intermediate pyrazole compound and a phenyl or pyridinyl derivative followed by cyclization of the resulting coupled intermediate to provide pyrimidin-7-ones. Synthetic routes for the preparation of certain pyrazole compounds are also described in Martins, M. A. P.; Freitag, R.; Flores, A. F. C.; Zanatta, N. Synthesis, 1995,1491 and Martins, M. A. P.; Flores, A. F. C.; Zanatta, N.; Bastos, G. P.; Bonacorso, H. G.; Siqueira, G. M. Tetrahedron Lett. 1999, 40,4309. In this processes the pyrazole compounds are prepared in two steps.
According to a first aspect of the invention, there is provided a novel xe2x80x9cone-potxe2x80x9d process for the production of pyrazole compounds of formula (II) 
wherein
RP is H or R1;
R1 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkyl((C1-C6)alkoxy), Het, (C1-C6)alkylHet, aryl, or (C1-C6)alkylaryl, which latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C1-C6)alkyl, C(O)NR4R5, C(O)R6, C(O)OR7, OR8, NR9aR9b and SO2NR10aR10b;
R2 is (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkyl((C1-C6)alkoxy), Het, (C1-C6)alkylHet, aryl, or (C1-C6)alkylaryl, which latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C1-C6)alkyl, C(O)NR4R5, C(O)R6, C(O)OR7, OR8, NR9aR9b and SO2NR10aR10b;
R3 is OH, (C1-C6)alkoxy, or NR4R5;
R4, R5, R6, R7, R8, R10a and R10b are each independently H or (C1-C6)alkyl;
R9a and R9b are each independently H, (C1-C6)alkyl, or taken together with the nitrogen atom to which they are attached form an azetidinyl, pyrollidinyl, or piperidinyl group;
wherein said process comprises the steps of
(i) reacting a compound of formula (III) 
where R11a and R11b are each independently (C1-C6)alkyl, R2 is as defined herein before, with an acylating agent of the formula (IV) in the presence of a base and an optional activating agent, 
where X is a halogen independently selected from Cl, F or Br, and Y is a halogen or OR12, where R12 is (C1-C6)alkyl, C(O)CX3, Het, or (C1-C6)alkyl(Het), where Het is pyridine or imidazole; and
(ii) adding in situ a hydrazine compound of formula (V) 
where RP is H or R1, where R1 is as defined hereinbefore, and Rx, Ry and Rz are each independently selected from H, an electron donating group (EDG: e.g., trialkylsilyl), or an electron withdrawing group (EWG: e.g., tert-butyloxycarbonyl and trifluoroacetamide) wherein the electron withdrawing group or electron donating group is labile under the conditions of the reaction. The process of the present invention provides advantages over the multi-step processes for the preparation of compounds of general formula (II) as described in EP 812 845, EP 994 115, WO 98/49166 and WO 99/54333.
The compounds of formula (II) can be represented by the formulae (IIA) and (IIB) as detailed hereinafter. 
The process described above is referred to herein as xe2x80x9cthe process of the inventionxe2x80x9d.
As used herein, the term xe2x80x9carylxe2x80x9d includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl and the like.
Het groups may be fully saturated, partly unsaturated, wholly aromatic, partly aromatic and/or bicyclic in character. Het groups that may be mentioned include groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl, imidazopyridinyl, piperazinyl, thienyl and furanyl.
The point of attachment of any Het group may be via any atom in the ring system including (where appropriate) a heteroatom. Het groups may also be present in the N- or S-oxidized form.
The term xe2x80x9c(C1-C6)alkylxe2x80x9d (which includes the (C1-C6)alkyl part of (C1-C6)alkylHet and (C1-C6)alkylaryl groups), when used herein, includes (e.g. methyl, ethyl, propyl, butyl, pentyl and hexyl groups). Unless otherwise specified, (C1-C6)alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched (e.g., iso-propyl, iso-butyl, sec-butyl, tert-butyl, isopentyl, neo-pentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, iso-hexyl, etc., including any stereoisomers thereof), or be saturated or unsaturated.
As defined herein, the term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d, unless specified otherwise, includes fluoro, chloro, bromo and iodo.
Suitable bases for use herein preferably include tertiary amines, such as triethylamine and di-iso-propylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, imidazole; substituted pyridines, such as 4-(dimethylamino)pyridine; benzofused pyridines, such as quinoline and isoquinoline; hindered metal alkoxides; hindered metal aryloxides; metal carbonates and bicarbonates.
Advantageously, in the process according to the present invention, the direct addition of the hydrazine compound (V) to the reaction vessel containing the reaction mixture of (III), (IV) and base results in production of compounds (II) with desirable purity and yield. Scheme 1 below outlines the general procedures of the synthesis. 
In a preferred aspect of the present invention there is provided a process for the production of pyrazole compounds of formula (II) 
wherein RP is H or R1, where R1 is (C1-C4)alkyl optionally substituted as hereinbefore described; R2 is (C1-C4)alkyl; R3 is (C1-C3)alkoxy, wherein the process comprises the step of (i) reacting a compound of formula (III), 
wherein R11a and R11b are each independently (C1-C4)alkyl and R2 is (C1-C4)alkyl, with an acylating agent of the formula (IV) in the presence of a base (preferably pyridine) and an optional activating agent 
where X is Cl or F, and Y is Cl, F or C(O)CX3; and
(ii) adding to the same vessel a hydrazine compound of formula (V), 
wherein RP is H or R1 where R1 is as defined hereinbefore, and Rx, Ry, and Rz are independently selected from H, an electron donating group, or an electron withdrawing group where the electron withdrawing group or the electron donating group is labile under the conditions of the reaction.
In a further preferred aspect of the present invention there is provided a process for the production of pyrazole compounds of formula (IIA), 
wherein RP is H or R1, where R1 is (C1-C4)alkyl optionally substituted as hereinbefore described; R2 is (C1-C4)alkyl; R3 is (C1-C3)alkoxy, wherein the process comprises the steps of (i) reacting a compound of formula (III), 
where R11a and R11b are each independently (C1-C4)alkyl and R2 is (C1-C4)alkyl, with an acylating agent of the formula (IV), 
where X is Cl or F, and Y is Cl, F or C(O)CX3, in the presence of a base (preferably pyridine) and an optional activating agent; and
(ii) adding in situ a hydrazine compound of formula (V) 
where RP is H or R1, where R1 is as defined hereinbefore, and Rx=EWG, Ry and Rz=H; or Rx and Ry=H and Rz=EDG; or Rx=Ry=Rz=H when R1=EWG; or Rx=EWG, Ry=H and Rz=EDG, wherein EWG is a tri(C1-C2)alkylsilyl group and EDG is tert-butyloxycarbonyl or trifluoroacetamide.
Scheme 2 illustrates the general procedures used in the synthesis of a compound of Formula (IIA). 
In yet another preferred aspect of the present invention there is provided a process for the production of pyrazole compounds of formula (IIB), 
wherein RP is H or R1, where R1 is (C1-C4)alkyl or (C1-C4)alkyl((C1-C2) alkoxy); R2 is (C1-C4)alkyl; and R3 is (C1-C3)alkoxy, wherein the process comprises the steps of (i) reacting a compound of formula (III) 
with an acylating agent of formula (IV) in the presence of pyridine and an optional activating agent 
where X and Y are each independently Cl or F; and (ii) adding after about 8 hours to about 24 hours a hydrazine compound of formula (V) 
wherein RP is H when
Rx=EWG, Ry and Rz=H; or
Rx and Ry=H and Rz=EDG; or
Rx=Ry=Rz=H when R1=EWG; or
Rx=EWG, Ry=H and Rz=EDG, where EDG is a tri(C1-C2)alkylsilyl group and EWG is tert-butyloxycarbonyl or trifluoroacetamide;
and RP is R1, where R1 is as defined hereinbefore, when Rx=H, Ry=H and Rz=EWG; or
Rx=EDG, Ry=H and Rz=H; or
Rx=Ry=Rz=H when R1=EDG; or
Rx=EDG, Ry=H and Rz=EWG, where EDG is a tri(C1-C2)alkylsilyl group and EWG is tert-butyloxycarbonyl or trifluoroacetamide.
Scheme 3 illustrates the general procedures used in the synthesis of a compound of Formula (IIB). 
The processes of the invention may be carried out in accordance with reaction conditions known to those skilled in the art.
The process according to the present invention may require an activating agent to xe2x80x9cactivatexe2x80x9d the compound of formula (III) and at least one equivalent of an acylating agent of formula (IV) to xe2x80x9creactxe2x80x9d with the activated compound generated from the compound of formula (III). Any suitable agent capable of activating the compound of formula (III) may be used in conjunction with at least one equivalent of acylating agent of formula (IV) according to the process of the present invention.
Preferably, the activating agent is capable of converting an acetal to an enol ether under the basic reaction conditions. Suitable activating agents include trialkylsilyl halides, trialkylsilyl trifluoromethanesulfonates, oxalyl halides, 2-(trifluoroacetoxy)pyridine, 1-(trifluoroacetyl)imidazole, trifluoroacetyl chloride, trifluoroacetic anhydride, tribromoacetyl chloride and trichloroacetyl chloride. More preferred activators include 2-(trifluoroacetoxy)pyridine, 1-(trifluoroacetyl)imidazole, trifluoroacetyl chloride, triflouroacetic anhydride, tribromoacetyl chloride and trichloroacetyl chloride.
In a preferred process of the present invention, the acylating agent of formula (IV) is used as both the activating agent and the acylating agent.
The acylating agent (IV) reacts with an enol ether to afford the key enone intermediate. Suitable reagents include be 2-(trifluoroacetoxy)-pyridine, 1-(trifluoroacetyl) imidazole, trifluoroacetyl chloride, trifluoroacetic anhydride, tribromoacetyl chloride and trichloroacetyl chloride. Preferred reagents include trifluoroacetic anhydride and trichloroacetyl chloride, even more preferred is trichloroacetylchloride.
Thus according to a yet further aspect of the present invention there is provided a process for the production of pyrazole compounds of formula (II), as defined hereinbefore, wherein the process comprises the steps of (i) reacting a compound of formula (III), as defined herein before, with at least one equivalent, more preferably at least two equivalents of an acylating agent of formula (IV), as defined hereinbefore, optionally in the presence of an activating agent, followed by the addition of a hydrazine compound of formula (V), as defined hereinbefore.
The reaction between the compound of the formula (III) and the activating agent (and/or the acylating agent of formula (IV), for reactions wherein the activating and acylating agents are the same) according to the process of the present invention may be carried out in an appropriate organic solvent system. The solvent system should not significantly react chemically with or significantly give rise to stereochemical changes in the reactants or product once formed, or significantly give rise to other side reactions. Suitable solvents include halogenated hydrocarbons (e.g., chloroform, dichloromethane and 1,2-dichloroethane), ethers (e.g., tetrahydrofuran, 1,4-dioxan, diethyl ether and tert-butyl methyl ether), aromatic hydrocarbons (e.g., toluene, xylenes and chlorobenzene) and alkyl acetates (e.g., ethyl acetate) and mixtures thereof. A preferred solvent is dichloromethane.
The reaction between the compound of formula (III) and the activating agent (and/or acylating agent of formula (IV)) according to the process of the present invention may be carried out at a temperature from about 0xc2x0 C. to about room temperature, and, preferably, in an inert atmosphere (i.e. in the presence of an inert gas, such as nitrogen or argon).
Following the activation and acylation of the compound of formula (III), the hydrazine compound of formula (V) is added directly to the reaction mixture (of the activating agent (and/or acylating agent of formula (IV)) and the compound of formula (III)) in situ to provide a compound of formula (II) according to the process of the present invention. The hydrazine compound (V) may be added portionwise, dropwise, in solution or neat. Typically, the hydrazine compound is added in water and/or a suitable organic solvent (e.g. alcohols such as methanol, ethanol or iso-propanol) to provide a compound of formula (II) wherein R3 is (C1-C6)alkoxy, or aqueous ammonia to provide a compound of formula (II) wherein R3 is NR4R5 or mixtures thereof, followed by removal of the original reaction solvent (e.g. dichloromethane) and heat treatment.
In reactions with hydrazine compounds of formula (V) where RP=R1 and R1 is an acid labile group such as a tert-butyloxycarbonyl group, the pH of the reaction mixture may be adjusted to between about pH 1.5 and about pH 3 and preferably to about pH 2 following addition of the hydrazine compound.
In reactions with hydrazine compounds of formula (V) where RP=H, it is not necessary to adjust the pH of the reaction mixture following the addition of the hydrazine compound.
In a yet further aspect of the process of the present invention, compounds of formula (II) where R3=OH may be prepared either via conversion of pyrazole compounds of formula (II) where R3=alkoxy as obtained according to the process described hereinbefore, or, alternatively via an in situ conversion (of the ester to the acid) where the pH of the reaction mixture is raised to greater than about pH 8 via addition of a suitable base (e.g, NaOH).
In yet another aspect of the process of the present invention, compounds of formula (II) prepared as outlined hereinbefore via (III), (IV) and (V) using aqueous ammonia as solvent (i.e. a compound of formula (II) where R3 is NR4R5), may be converted directly to provide a compound of the formula B (as illustrated in Scheme 1 above).
Appropriate reaction times and reaction temperatures depend upon the solvent system that is employed, as well as the compound that is to be formed, but these may be determined routinely by the person skilled in the art.
Compounds of formula (III) when not commercially available may be prepared by known techniques as detailed in the preparations section herein.
Compounds of formulae (IV) and (V), and derivatives thereof, when not commercially available or not subsequently described, may be obtained by conventional synthetic procedures or by analogy with the processes described herein, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
According to a further aspect of the present invention, the compounds of formula (I): 
or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, wherein
A is CH or N;
R1 is H, (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, or (C1-C3)perfluoroalkyl, wherein the alkyl group may be branched or straight chain and wherein the alkyl, alkenyl, cycloalkyl or perfluoroalkyl group is optionally substituted by one or more substituents selected from hydroxy, (C1-C4)alkoxy, (C3-C6)cycloalkyl, (C1-C3)perfluoroalkyl, phenyl substituted with one or more substitutents selected from (C1-C3)alkyl, (C1-C4)alkoxy, (C1-C4)haloalky, or (C1-C4)haloalkoxy, wherein the haloalkyl and haloalkoxy groups contain one or more halo atoms, halo, CN, NO2, NHR11, NHSO2R12, SO2R12, SO2NHR11, COR11, CO2R11 (where R11 is H, (C1-C4)alkyl, (C2 -C4)alkenyl, (C1-C4)alkanoyl, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy and R12 is (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkanoyl, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy), NR7R8, CONR7R8 or NR7COR11 (where R7 and R8 are each independently selected from H, (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, CO2R9, SO2R9 wherein the alkyl, alkenyl or alkoxy groups are optionally substituted by NR5R6, (C1-C4)haloalkyl, or (C1-C4)haloalkoxy and R9 is H, hydroxy(C2-C3)alkyl, (C1-C4)alkanoyl, or (C1-C4)alkyl optionally substituted with phenyl wherein the phenyl group is optionally substituted by one or more substituents selected from (C1-C4)alkyl (optionally substituted with (C1-C4)haloalkyl or (C1-C4)haloalkoxy, (C1-C4)alkoxy, halo, CN, NO2, NHR11, NHSO2R12, SO2R12, SO2NHR11, COR11 or CO2R11), Het1, Het2, or Het3; or
R1 is Het4 or phenyl wherein the phenyl group is optionally substituted by one or more substituents selected from (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, halo, CN, CF3, OCF3, NO2, NHR11, NHSO2R12, SO2R12, SO2NHR11, COR11, or CO2R11;
R2 is H, (C1-C6)alkyl, (C3-C6)alkenyl, or (CH2)n((C3-C6)cycloalkyl) where n is 0, 1, or 2 and the alkyl or alkyenyl group is optionally substituted with one or more fluoro substituents;
R13 is OR3 or NR5R6;
R3 is (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)perfluoroalkyl, or ((C3-C6)cycloalkyl) (C1-C6)alkyl optionally substituted with one or two substituents selected from (C3-C5)cycloalkyl, hydroxy, (C1-C4)alkoxy, (C3-C6)alkenyl, (C3-C6)alkynyl, benzyloxy, NR5R6, phenyl, Het1, Het2, Het3, or Het4 wherein the (C1-C6)alkyl and (C1-C4)alkoxy groups may optionally be terminated by a haloalkyl group (e.g., CF3), (C3-C6)cycloalkyl, Het1, Het2, Het3, or Het4;
R4 is (C1-C4)alkyl optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7, (C2-C4)alkenyl optionally substituted with CN, CONR5R6 or CO2R7, (C2-C4)alkanoyl optionally substituted with NR5R6, hydroxy(C2-C4)alkyl optionally substituted with NR5R6, ((C2-C3)alkoxy)(C1-C2)alkyl optionally substituted with OH or NR5R6, CONR5R6, CO2R7, halo, NR5R6, NHSO2NR5R6, NHSO2R8, phenyl optionally substituted with methyl, or heterocyclyl optionally substituted with methyl, or
R4 is a pyrrolidinylsulphonyl, piperidinosulphonyl, morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a substituent R10 at the 4-position of the piperazinyl group wherein the piperazinyl group is optionally substituted with one or two (C1-C4)alkyl, (C1-C3)alkoxy, NR7R8, or CON R7R8 groups and is optionally in the form of its 4-N-oxide;
R5 and R6 are each independently selected from H or (C1-C4)alkyl optionally substituted with (C3-C5)cycloalkyl, (C1-C4)alkoxy, or taken together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-(NR9)- piperazinyl or imidazolyl group wherein the group is optionally substituted with methyl or hydroxy;
R10 is H, (C1-C6)alkyl, ((C1-C3)alkoxy)(C2-C6 )alkyl, hydroxy(C2-C6)alkyl, (R7R8N)(C2-C6)alkyl, (R7R8NCO)(C1-C6)alkyl, CONR7R8, CSNR7R8 or C(NH)NR7R8 optionally substituted with one or two substituents selected from hydroxy, NR5R6, CONR5R6, phenyl optionally substituted with (C1-C4)alkyl or (C1-C4)alkoxy, (C2-C6)alkenyl, or Het4;
Het1 is an N-linked 4-, 5- or 6-membered nitrogen-containing heterocyclic group optionally containing one or more further heteroatoms selected from S, N or O;
Het2 is a C-linked 5-membered heterocyclic group containing an O, S or N heteroatom optionally containing one or more heteroatoms selected from O or S;
Het3 is a C-linked 6-membered heterocyclic group containing an O or S heteroatom optionally containing one or more heteroatoms selected from O, S or N or Het3 is a C-linked 6-membered heterocyclic group containing three N heteroatoms;
Het4 is a C-linked 4-, 5- or 6-membered heterocyclic group containing one, two or three heteroatoms selected from S, O or N; and
wherein any of the heterocyclic groups Het1, Het2, Het3 or Het4 may be saturated, partially unsaturated or aromatic and any of the heterocyclic groups may be optionally substituted with one or more substituents selected from (C1-C4)alkyl, (C2-C4)alkenyl, (C1-C4)alkoxy, halo, CO2R11, COR11, SO2R12 or NHR11 and/or any of the heterocyclic groups is benzo-fused;
or when R13 is OR or R3NR5, then
R1 is Het, (C1-C6)alkylHet, aryl or (C1-C6)alkylaryl, which latter four groups are all optionally substituted with one or more substituents selected from halo, cyano, nitro, (C1-C6)alkyl, halo((C1-C6)alkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 or SO2NR14R15;
R2 is H, halo, cyano, nitro, OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13, SO2NR14R15, (C1-C6)alkyl, Het, (C1-C6)alkylHet, aryl or (C1-C6)alkylaryl, which latter five groups are all optionally substituted with one or more substituents selected from halo, cyano, nitro, (C1-C6)alkyl, halo((C1-C6)alkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 or SO2NR14R15;
R3 is H, (C1-C6)alkyl, (C1-C6)alkylHet, or (C1-C6)alkylaryl, which latter three groups are all optionally substituted with one or more substituents selected from halo, cyano, nitro, (C1-C6)alkyl, halo((C1-C6)alkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12 R13 or SO2NR14R15;
R4 is H, halo, cyano, nitro, halo((C1-C6)alkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13, NR16Y(O)R17, SOR18, SO2R19R20, C(O)AZ, (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, Het, (C1-C6)alkylHet, aryl, (C1-C6)alkylaryl, which latter seven groups are all optionally substituted with one or more substituents selected from halo, cyano, nitro, (C1-C6)alkyl, halo((C1-C6)alkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 or SO2NR14R15;
Y is C or S(O), wherein one of R16 and R17 is not present when Y is S(O);
A is (C1-C6)alkylene;
Z is OR6, halo, Het or aryl, which latter two groups are both optionally substituted with one or more substituents selected from halo, cyano, nitro, (C1-C6)alkyl, halo((C1-C6)alkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 or SO2NR14R15;
R5, R6, R7, R8, R9, R18, R19 and R20 are each independently H or (C1-C6)alkyl;
R10 and R11 are each independently H, (C1-C6)alkyl optionally substituted with one or more substituents selected from halo, cyano, nitro, (C1-C6)alkyl, halo((C1-C6)alkyl), OR6, OC(O)R7, C(O)R , C(O)OR9, C(O)NR10R11, NR12R13, or SO2NR14R15, Het or aryl optionally substituted with one or more substituents selected from halo, cyano, nitro, (C1-C6)alkyl, halo((C1-C6)alkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13, or SO2NR14R15, or one of R10 and R11 may be (C1-C6)alkoxy, amino, or Het, which latter two groups are both optionally substituted with (C1-C6)alkyl;
R12 and R13 are each independently H or (C1-C6)alkyl, or one of R12 or R13 may be C(O)-(C1-C6)alkyl or C(O)Het in which Het is optionally substituted with (C1-C6)alkyl;
R14 and R15 are each independently H or (C1-C6)alkyl, or R14 and R15 taken together with the nitrogen atom to which they are bound form a heterocyclic ring;
R16 and R17 are each independently H or (C1-C6)alkyl, or one of R16 and R17 may be Het or aryl, which latter two groups are both optionally substituted with (C1-C6)alkyl;
Het is an optionally substituted four to twelve membered heterocyclic group, which may be aromatic or non-aromatic, contain one or more double bonds, mono- or bi-cyclic and contains one or more heteroatoms selected from the group consisting of N, S and O;
wherein the compounds may be prepared from compounds of formula (VIII) 
wherein R1, R2, R4 and R13 are as defined hereinbefore and the compound of formula (VIII) is prepared from the reaction of a compound of formula (VII), 
where R 4 and R 13 are as defined herein before, via coupling with a compound of formula (VI), 
where R1 and R2 are as defined hereinbefore and R1 is NRpRq, where Rp and Rq are each independently H or (C1-C6)alkyl, and the compound of formula (VI) is prepared by nitration and hydrogenation of a compound of formula (II), 
where Rt and R2 are as defined hereinbefore and RP is R1 as defined hereinbefore,
wherein the compound of formula (II) is prepared by reacting in the presence of a base and an optional activating agent a compound of formula (III), 
where R11a and R11b are each independently (C1-C6)alkyl and R2 is as defined herein before, with an acylating agent of formula (IV), 
where X is halogen independently selected from Cl, F or Br, and Y is halogen or OR12 where R12 is (C1-C6)alkyl, C(O)CX3, Het, or (C1-C6)alkyl(Het) where Het is pyridine or imidazole; and then adding in situ a hydrazine compound of formula (V), 
where RP is H or R1 where R1 is as defined hereinbefore, and Rx, Ry and Rz are each independently selected from H, an electron donating group (EDG), or an electron withdrawing group (EWG) where the electron withdrawing group or the electron donating group is labile under the conditions of the reaction.
According to a preferred process of the present invention, compounds of formula (I) are prepared from compounds of formula (II) wherein R1is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkyl((C1-C6)alkoxy), Het, (C1-C6)alkylHet, aryl or (C1-C6)alkylaryl, which latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C1-C6)alkyl, C(O)NR4R5, C(O)R6, C(O)OR7, OR8, NR9aR9b and SO2NR10aR10b;
R2 is (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkyl((C1-C6)alkoxy), Het, (C1-C6)alkylHet, aryl, or (C1-C6)alkylaryl, which latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C1-C6)alkyl, C(O)NR4R5, C(O)R6, C(O)OR7, OR8, NR9aR9b and SO2NR10aR10b;
Rt is NRPRq;
RP, Rq, R6, R7, R8, R10a and R10b are each independently H or (C1-C6)alkyl;
R9a and R9b are each independently H, (C1-C6)alkyl or taken together with the nitrogen atom to which they are attached form an azetidinyl, pyrollidinyl or piperidinyl group;
R4 is CO2R7, (C1-C4)alkyl optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7, or
R4 is a pyrrolidinylsulphonyl, piperidinosulphonyl, morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a substituent, R10 at the 4-position of the piperazinyl group wherein the piperazinyl group is optionally substituted with one or two (C1-C4)alkyl, (C1-C3)alkoxy, NR7R8 or CON R7R8 groups and is optionally in the form of its 4-N-oxide; and
R10 is H or (C1-C6)alkyl.
A highly preferred process for the preparation of compounds of formula (I) from compounds of formula (II) is when R1 is (C1-C4)alkyl, where alkyl group is optionally interrupted by an oxygen atom and/or is optionally terminated by a Het group (such as a pyridinyl group);
R2 is (C1-C4)alkyl;
R3 is (C1-C5)alkyl optionally interrupted by an oxygen atom;
R4 is CO2R7, or a morpholinosulphonyl or piperazin-1-ylsulphonyl group having a substituent R10 at the 4-position of the piperazinyl group where R10 is H, methyl, or ethyl.
More preferred compounds of formulae 1, IA and IB prepared according to a process of the present invention include those in which R1 is a linear (C1-C3)alkyl optionally interrupted by an oxygen atom, or is optionally terminated by a 2-pyridinyl group (e.g. to form a 2-pyridinylmethyl group);
R2 is a linear (C2-C3)alkyl;
R3 is a linear or branched (C2-C4)alkyl optionally interrupted by an oxygen atom;
R4 is CO2R7, or a morpholinosulphonyl or piperazin-1-ylsulphonyl group having a substituent R10 at the 4-position of the piperazinyl group where R10 is methyl or ethyl.
Particularly preferred compounds that may be formed according to a process of the present invention include sildenafil (1A), and the following five compounds: 
Compound 1B is also known as (+)-3-ethyl-5-[5-(4-ethylpiperazin-1 -ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or alternatively as 3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl)-}2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (the compound of Example 118 of WO99/54333).
Compound 1C is also known as 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (the compound of Example 5 of WO98/49166).
Compound 1D is also known as 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (the compound of Example 4 of WO99/54333).
Compound 1E is also known as 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or alternatively as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridyl sulphonyl}-4-ethylpiperazine (the compound of Example 103 of WO 01/27113 and exemplified hereinafter as Example 1).
Compound 1F is also known as 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (the compound of Example 132 of WO 01/27112 and exemplified hereinafter as Example 2).
Compounds of formulae (II) may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. The process of the invention thus also relates to the formation of stereoisomers of compounds of formulae II and mixtures thereof. Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively, the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions that will not cause racemization or epimerization, or by derivatization, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, crystallisation, chromatography over silica or, for example, via classical resolution with a homochiral acid salt). The formation of all stereoisomers is included within the scope of the invention.
Compounds may be isolated from reaction mixtures using known techniques.
Substituents on the aryl (e.g. phenyl), and (if appropriate) heterocyclic, group(s) in compounds defined herein may be converted to other substituents using techniques well known to those skilled in the art. For example, amino may be converted to amido, amido may be hydrolysed to amino, hydroxy may be converted to alkoxy, alkoxy may be hydrolyzed to hydroxy etc.
It will be appreciated by those skilled in the art that in the processes described above the functional groups of intermediate compounds may be or may need to be protected by protecting groups.
Functional groups that may be desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups). Suitable protecting groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include (C1-C6)alkyl, allyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J W F McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3rd edition, T W Greene and P G M Wutz, Wiley-Interscience (1999).
The process of the invention possesses the advantage that the intermediate pyrazoles of formula (II) that are used in the synthesis of pyrimidin-7-ones, and in particular in the preparation of sildenafil (compound (IA) herein) may be prepared from commercially-available starting materials in fewer steps than in processes described in the prior art without concomitant losses in yield of key intermediates and of final compounds. Further, the pyrazoles are obtained in desirable levels of purity according to the process of the present invention.
Further, the process of the invention may have the advantage that pyrazole compounds of formula (II) may be prepared in less time, more conveniently, and at a lower cost than when prepared in processes described in the prior art.
The invention is illustrated, but in no way limited, by the following examples.